The invention relates to a method and apparatus to determine and monitor the concentration of tissue glucose as defined in the preambles of the independent claims 1 and 17.
Methods of this kind are applicable foremost in human medicine, in particular to monitor the blood sugar of diabetics. They are based on the insight that the glucose content of the interstitial tissue fluid is highly correlated, with little time delay, to the blood sugar level. It is known to recover glucose by dialysis and then to determine the glucose content by enzymatic-amperometric measurements in an flow-through test cell. For that purpose a continuous flow of perfusate is made to pass along the dialysis membrane of the dialysis probe. The yield so obtained depends essentially on the rate of perfusion and as a rule is less than 30%. The measurement is commensurately inaccurate because interfering factors such as tissue movement and changes in blood circulation strongly affect the yield and hence the test signal. Lowering the perfusion rate will not help because entailing a correspondingly higher dead time caused by the flow time between the microdialysis probe and the test site. On the other hand, high rates of flow velocity do indeed lower the dead time. However the dialysis yield relative to a unit volume of perfusion solution decreases to the same extent. Moreover a glucose gradient is formed in the tissue surrounding the microdialysis probe on account of continuously withdrawing glucose. However long-term treatment of diabetics mandates reliable glucose measurements to dose insulin administrations as needed and, where desirable, automatically.
Based on the above, the objective of the invention is to create a method and apparatus of the initially cited kinds which offer high reliability and accuracy as regards glucose determination.
The combinations of features stated in the patent claims 1 and 17 are proposed as solutions. Further advantageous implementations of the invention are stated in the dependent claims.
The conventional continuous enrichment of the perfusion solution is replaced in the invention by equalizing the liquid column, moved in segments with high yield through the microdialysis probe, and the tissue glucose content. Accordingly the invention proposes to reduce the time-averaged volumetric flow of the perfusion solution for the duration of dialysis intervals and that the volume of perfusion solution perfused during each dialysis interval through the microdialysis probe shall be moved on in an ensuing transport interval at a higher volumetric flow to the test cell. The equalization of concentration taking place during the dialysis intervals averts continuous impoverishment of the tissue. At the same time, high signal strength is achieved because of the higher yield. The enriched partial volumes can be moved at a higher conveyance flow and thus with a lesser dead time to the test cell.
In a preferred implementation of the invention, the perfusion solution is mixed with glucose before being made to pass through the microdialysis probe and a predetermined initial concentration is set, preferably within the physiological range. Using an initial solution mixed with glucose leads to diffusion enrichment or impoverishment at the dialysis membrane depending on the tissue glucose concentration. Accordingly a signal peak or a signal dip is observed in the time-sequence of the test signals at the test cell. On the other hand the subsequent perfusion solution passing at a higher flow during the transport intervals through the microdialysis probe essentially retains its initial glucose concentration. Accordingly a base line reflecting the initial glucose concentration is picked up during the subsequent flow through the cell.
Advantageously the volumetric flow of perfusion solution is so adjusted during the transport intervals that the glucose content of the perfusion solution changes less than 10%, preferably less than 5%, on account of the reduced duration of dialysis, when passing through the microdialysis probe. On the other hand, in order to increase the accuracy of measurement, the volumetric flow during the dialysis intervals should be adjusted in such manner that the glucose content of the perfusion solution essentially matches the concentration of tissue glucose when passing through the microdialysis probe.
Advantageously a base line value is determined from the test signals picked up at the test cell during the flow-through of the volume of the perfusion solution perfused at higher-volumetric flow, said base line value reflecting the initial glucose concentration and thereby allowing continuous signal correction for instance in the event of fluctuations in test sensitivity.
Advantageously the peak test signals ascertained during the transport intervals at the test cell when crossed by the enriched liquid-column segments are evaluated with respect to their extreme value, hereafter called extremum/extrema, or of their integrated value, to determine the tissue glucose concentration.
Advantageously the tissue glucose concentration is determined in each transport interval from the ratio of the extremum to the base line value of the test signal multiplied by the value of initial glucose concentration and where called for by a predetermined calibration value. This procedure allows constantly updated calibration of the glucose test values and compensating any signal drifts. In this manner spurious measurements can be precluded that otherwise might arise from conveyance malfunctions or interferences in the test cell.
Because of the peak-shaped signal sequence of the test signals, validity testing is feasible in that the predetermined time between the extrema of the test signals will be monitored by the time between the transport intervals.
Advantageously again, the signal sequence of the test signals is used for validity-checking the ascertained glucose content, a peak being expected as a valid signal shape when comparing a concentration value higher than the initially set glucose concentration and a dip for a lesser value of concentration. In this manner reliable, qualitative checking of the measurements is possible. Another increase in reliability of measurement can be achieved in that the initial glucose concentration is set to a sugar deficiency value and in that when the test signals undergo a dip in their sequence, a sugar-deficiency alarm is triggered. Moreover it is basically feasible to adjust the initial glucose concentration in phases alternatinglyxe2x80x94for instance using a valve circuitxe2x80x94to a sugar deficiency value and an excess sugar value, an alarm signal being emitted at a dip during the phase of adjusted sugar deficiency value and at a peak during the phase of adjusted excess sugar value.
Qualitative pattern recognition in the sequence of the test signals is implemented in simple manner in that the extrema ascertained in the time between the transport intervals are compared with the particular associated base line value, where a peak shall be recognized when comparing an extremum larger than the base line value and a dip shall be recognized when comparing an extremum smaller than the base line value.
In another preferred implementation of the invention, the perfusion solution is moved during the dialysis intervals always in several, time-separated conveyed batches through the microdialysis probe. Thereby the glucose-enriched segment of the liquid column is widened and correspondingly the diffusion decay will be reduced during the ensuing transport interval.
When seeking high yield in the dialysis, advantageously a volume of the perfusion solution substantially corresponding to the volume of the microdialysis probe is moved at each conveyed batch. Another improvement can be achieved in this respect by so sizing the conveyance pauses between conveyed batches that the glucose content of the perfusion-solution volume instantaneously present in the microdialysis probe shall substantially equal the tissue glucose concentration.
In an alternative to the batch-conveyance, the volumetric flow of the perfusion solution may be reduced to a constant value for the duration of the dialysis intervals.
The initially cited problem regarding the measurement apparatus is solved in that at least one glucose reservoir containing glucose in a predetermined initial concentration can be connected to the perfusate line. In order to ascertain whether the tissue glucose represents a deficiency or excess of sugar, two glucose reservoirs separately connectable to the perfusate line may be used, each containing dissolved glucose of a different concentration.
Advantageously the at least one glucose reservoir shall be connectable through a switching valve to the perfusate line to allow mixing the perfusion solution selectively at separate times and/or if called for at a different concentration to the perfusate line.
A defined batch-wise conveyance of the perfusion solution, which may be enriched with glucose, can be implemented by using a metering pump preferably operated at intervals as the conveyor unit.